論文 - 詳細
| RRC ID | 58075 |
|---|---|
| 著者 | Moro H, Hattori N, Nakamura Y, Kimura K, Imai T, Maeda M, Yashiro M, Ushijima T. |
| タイトル | Epigenetic priming sensitizes gastric cancer cells to irinotecan and cisplatin by restoring multiple pathways. |
| ジャーナル | Gastric Cancer |
| Abstract |
BACKGROUND:Gastric cancer is heavily influenced by aberrant DNA methylation that alters multiple cancer-related pathways, and may respond to DNA demethylating agents, such as 5-aza-2'-deoxycytidine (5-aza-dC). Here, we aimed to analyze whether 5-aza-dC can sensitize gastric cancer cells to clinically used cytotoxic drugs. METHODS:Ten gastric cancer cell lines were treated with 5-aza-dC for 72 h and their growth was analyzed by conducting WST assay. In vivo effect of the drugs was analyzed using xenografts of OCUM-2 M/SN38 cells. Genome-wide expression and DNA methylation analyses were conducted using microarrays, and biological functions were identified through ingenuity pathway analysis. RESULTS:The cell lines most resistant to SN38 (an active metabolite of irinotecan), CDDP, PTX, and 5-FU, were identified. 5-Aza-dC pre-treatment of the resistant cell lines decreased the IC50 values for SN38 (TMK1, 226.4 nM to 32.91 nM; 44As3, 128.2 nM to 19.32 nM; OCUM2 M/SN38, 74.43 nM to 16.47 nM) and CDDP (TMK1, 5.05 µM to 2.26 µM; OCUM2 M, 10.79 µM to 2.77 µM), but not PTX and 5-FU. The reactivation of apoptosis-related genes, such as RUNX3, PYCARD, TNF, FAS, and FASLG, was induced by pre-treatment with 5-aza-dC, and the DNA demethylation of promoter CpG islands of RUNX3 and PYCARD was confirmed. In a xenograft model with OCUM2 M/SN38, treatment with 5-aza-dC before irinotecan showed markedly enhanced tumor suppression. CONCLUSION:Epigenetic priming with 5-aza-dC can improve the sensitivity of gastric cancer cells to SN38 and CDDP. |
| 巻・号 | 23(1) |
| ページ | 105-115 |
| 公開日 | 2020-1-1 |
| DOI | 10.1007/s10120-019-01010-1 |
| PII | 10.1007/s10120-019-01010-1 |
| PMID | 31555951 |
| MeSH | Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology* Cell Line, Tumor Cisplatin / administration & dosage DNA Methylation / drug effects Decitabine / administration & dosage Drug Resistance, Neoplasm / drug effects* Drug Resistance, Neoplasm / genetics Epigenesis, Genetic / drug effects* Female Gene Expression Regulation, Neoplastic / drug effects Humans Irinotecan / administration & dosage Mice, Nude Stomach Neoplasms / drug therapy* Stomach Neoplasms / genetics* Xenograft Model Antitumor Assays |
| IF | 7.088 |
| 引用数 | 2 |
| リソース情報 | |
| ヒト・動物細胞 | MKN1(RCB1003) |